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To elucidate the brain effects of psilocybin, we directly compared the acute effects of 5-HT2AR agonist (psilocybin) and antagonist (ketanserin) on cerebral blood flow (CBF) using pseudo-continuous arterial spin labeling magnetic resonance imaging (MRI) in a single-blind, cross-over study in 28 healthy participants. We evaluated associations between plasma psilocin level (PPL) or subjective drug intensity (SDI) and CBF. We also evaluated drug effects on internal carotid artery (ICA) diameter using time-of-flight MRI angiography. PPL and SDI were significantly negatively associated with regional and global CBF (\u223c11.6% at peak drug effect, p\u2009&lt;\u20090.0001). CBF did not significantly change following ketanserin (2.3%, p\u2009=\u20090.35). Psilocybin induced a significantly greater decrease in CBF compared to ketanserin in the parietal cortex (p\n                    <jats:sub>FWER<\/jats:sub>\n                    \u2009&lt;\u20090.0001). ICA diameter was significantly decreased following psilocybin (10.5%, p\u2009&lt;\u20090.0001) but not ketanserin (\u22120.02%, p\u2009=\u20090.99). Our data support an asymmetric 5-HT2AR modulatory effect on CBF and provide the first in vivo human evidence that psilocybin constricts the ICA, which has important implications for understanding the neurophysiological mechanisms underlying its acute effects.\n                  <\/jats:p>","DOI":"10.1177\/0271678x251323364","type":"journal-article","created":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T03:50:56Z","timestamp":1740541856000},"page":"1385-1401","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":14,"title":["Acute psilocybin and ketanserin effects on cerebral blood flow: 5-HT2AR neuromodulation in healthy humans"],"prefix":"10.1177","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4437-6248","authenticated-orcid":false,"given":"Kristian","family":"Larsen","sequence":"first","affiliation":[{"name":"Neurobiology Research Unit and NeuroPharm, Rigshospitalet, Copenhagen, Denmark"},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Lindberg","sequence":"additional","affiliation":[{"name":"Functional Imaging Unit, Department of Clinical Physiology and Nuclear Medicine, Rigshospitalet, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brice","family":"Ozenne","sequence":"additional","affiliation":[{"name":"Neurobiology Research Unit and NeuroPharm, Rigshospitalet, Copenhagen, Denmark"},{"name":"Department of Public Health, Section of Biostatistics, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6360-5224","authenticated-orcid":false,"given":"Drummond E","family":"McCulloch","sequence":"additional","affiliation":[{"name":"Neurobiology Research Unit and NeuroPharm, Rigshospitalet, Copenhagen, Denmark"},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia","family":"Armand","sequence":"additional","affiliation":[{"name":"Neurobiology Research Unit and NeuroPharm, Rigshospitalet, Copenhagen, Denmark"},{"name":"Department of Psychology, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin K","family":"Madsen","sequence":"additional","affiliation":[{"name":"Neurobiology Research Unit and NeuroPharm, Rigshospitalet, Copenhagen, Denmark"},{"name":"Department of Psychiatry, University Hospital Svendborg, Svendborg, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0264-2368","authenticated-orcid":false,"given":"Annette","family":"Johansen","sequence":"additional","affiliation":[{"name":"Neurobiology Research Unit and NeuroPharm, Rigshospitalet, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dea S","family":"Stenb\u00e6k","sequence":"additional","affiliation":[{"name":"Neurobiology Research Unit and NeuroPharm, Rigshospitalet, Copenhagen, Denmark"},{"name":"Department of Psychology, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gitte M","family":"Knudsen","sequence":"additional","affiliation":[{"name":"Neurobiology Research Unit and NeuroPharm, Rigshospitalet, Copenhagen, Denmark"},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8115-0611","authenticated-orcid":false,"given":"Patrick M","family":"Fisher","sequence":"additional","affiliation":[{"name":"Neurobiology Research Unit and NeuroPharm, Rigshospitalet, Copenhagen, Denmark"},{"name":"Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2025,2,26]]},"reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2215-0366(16)30065-7"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2020.3285"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2206443"},{"key":"e_1_3_6_5_2","doi-asserted-by":"publisher","DOI":"10.1177\/0269881116675513"},{"key":"e_1_3_6_6_2","doi-asserted-by":"publisher","DOI":"10.1001\/archgenpsychiatry.2010.116"},{"key":"e_1_3_6_7_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2022.2096"},{"key":"e_1_3_6_8_2","doi-asserted-by":"publisher","DOI":"10.1177\/0269881114548296"},{"key":"e_1_3_6_9_2","doi-asserted-by":"crossref","unstructured":"McCulloch DE-W Grzywacz MZ Madsen MK et al. 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